Date Published: June 23, 2017
Publisher: Public Library of Science
Author(s): Nathan P. Ward, Angela M. Poff, Andrew P. Koutnik, Dominic P. D’Agostino, Jianhua Zhang.
The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin’s reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in VM-M3 GBM cells. Metformin potentiated DCA-induced superoxide production, which was required for enhanced cytotoxicity towards VM-M3 cells observed with the combination. Similarly, rotenone enhanced oxidative stress resultant from DCA treatment and this too was required for the noted augmentation of cytotoxicity. Adenosine monophosphate kinase (AMPK) activation was not observed with the concentration of metformin required to enhance DCA activity. Moreover, addition of an activator of AMPK did not enhance DCA cytotoxicity, whereas an inhibitor of AMPK heightened the cytotoxicity of the combination. Our data indicate that metformin enhancement of DCA cytotoxicity is dependent on complex I inhibition. Particularly, that complex I inhibition cooperates with DCA-induction of glucose oxidation to enhance cytotoxic oxidative stress in VM-M3 GBM cells.
A consequence of the hallmark metabolic alterations associated with neoplastic growth is elevated oxidative stress . Hypoxia, mitochondrial abnormalities, and organellar inputs, such as ER stress, not only direct cancer metabolism but also greatly influence the generation of reactive oxygen species (ROS) and oxidative stress [2, 3]. Concurrently, these energetic and redox stresses dictate a compensatory increase in antioxidant capacity that permits cancer cell resilience and proliferation .
Warburg metabolism, characterized by the aerobic fermentation of glucose, is hallmark of many cancers, including GBM [4, 40]. Among the confluence of factors that contribute to this distinct metabolic phenotype is the maintenance of PDH complex phosphorylation . This is mediated by enhanced PDK activity, the inhibitory kinase of the PDH complex. Pharmacological activation of this complex with the small molecule PDK inhibitor, DCA, has been shown to reduce tumor growth and promote cancer cell death through induction of oxidative stress [18, 19].
Our results provide further evidence for potential synergy between DCA and metformin in targeting GBM. Specifically, that modulation of redox balance through insult of mitochondrial metabolic efficiency is a potential anti-cancer strategy that merits further evaluation. This combination may be particularly useful as an adjuvant to current pro-oxidant therapies, for which efficacy is often fleeting due to chemoresistant mechanisms that restrict mitochondrial oxidation [13, 14, 16, 20].